This invention relates to methods for treating diseases of the central and peripheral nervous systems.
There is a remarkable propensity for accumulation of calcium and other multivalent cations in the basal ganglia and dentate nucleus of man. In a majority of cases, calcium deposits are asymptomatic, but there are still many cases in which a devastating, slowly progressive Parkinson-like disorder is associated with dense coalescence of calcium deposits into xe2x80x9cbrain stonesxe2x80x9d (1). Pathologically, brain stones are found mostly in the grey matter of the basal ganglia, and chemical analysis reveals that they are composed mostly of hydroxyapatite, which is the same calcium-phosphate structure of normal bone (1, 2).
Such cerebral calcifications have been associated with hypoparathyroidism, mitochondrial myopathies, and an idiopathic, familial form of basal ganglia calcification that often carries the eponym of Fahr Disease (1-4). In Fahr disease, cerebral calcification is observed in teenage children, however, patients do not begin developing progressive parkinsonian and psychiatric symptoms until reaching their 30""s and 40""s. No clear underlying defect in calcium or phosphate metabolism has been established for these patients, and there is, as yet, no treatment for the progressive neurologic deterioration of this disease.
Bisphosphonates are a class of drugs that resemble pyrophosphoric acid and are used for treatment of diseases of bone and calcium metabolism (5). They have been used with variable success for ectopic, subcutaneous calcification, and are generally considered to be safe, with few side effects. In vitro, bisphosphonates have been shown to have a high affinity for solid-phase calcium phosphate, and thereby inhibit both the formation and dissolution of hydroxyapatite.
I have found that a class of drugs, called bisphosphonates, and the specific drug, disodium etidronate, are useful therapeutic agents for diseases of the human central and peripheral nervous systems that are associated with abnormal calcifications within the nervous system.
Accordingly, the invention provides methods of treating a patient having a disease of the nervous system characterized by abnormal calcification, by administering a bisphosphonate the patient. Treatment according to the methods of the invention results in improvement of a symptom(s) of a treated patient.
Patients that can be treated using the methods of the invention include those at all stages of development of a disease of the nervous system characterized by calcification within the nervous system. For example, treatment of an older patient with Fahr disease is described in detail below. Treatment of younger, less disabled patients with this disorder offers an alternative, more favorable course to an otherwise devastating neurologic disease.
An example of a bisphosphonate that can be used in the methods of the invention is disodium etidronate, which can be administered, for example, orally in an amount between 5-20 mg/kg/day (e.g., 10-15 mg/kg/day). Other bisphosphonates are known in the art, and can be used in the methods of the invention. For example, pamidronate, risedronate, ibandronate, olpadronate, incadronate, neridronate, tiludronate, can be used, and proper modes of administration (e.g., oral or intravenous infusion) and dosages of these drugs are known to those of skill in the art. Administration of combinations of these drugs can also be carried out.
In the methods of the invention, bisphosphonates are used to treat diseases of the nervous system in which calcifications occur within the nervous system. The mechanism of action of these agents in treating these diseases is to prevent the further growth of calcifications, and to reduce neurological symptoms related to the calcifications. Used in this fashion, bisphosphonates improve neurological function, reduce seizures, and improve abnormal behaviors.
An example of a particular disease that can be treated by the methods of the invention is Fahr disease, which is characterized by idiopathic cerebral calcification of the basal ganglia. Other examples of diseases of the nervous system that can be treated with bisphosphonates according to the invention are as follows: post-radiation-induced calcifications of the brain; post-stroke/hypoxemic calcifications; calcified brain tumors, primary and metastatic; neurocysticercosis; human immunodeficiency virus (HIV)-induced calcifications of the brain; cytomegalovirus infection; cryptococcosis of the central nervous system; other post-infectious calcifications of the brain (e.g., as is found in tuberculosis and toxoplasmosis); metabolic disease-induced cerebral calcification; endocrine disease-induced cerebral calcification (hypoparathyroidism, etc.); celiac disease; mitochondrial encephalomyopathies; subdural hematoma with calcifications; other seizure disorders associated with cerebral calcifications; arteriovenous malformations of the brain; cerebral lupus and other forms of vasculitis associated with cerebral calcifications; and presenile dementia with associated cerebral calcifications.
Other features and advantages of the invention will be apparent from the following detailed description, the drawings, and the claims.